Blockade of T cell costimulation reveals interrelated actions of CD4+ and CD8+ T cells in control of SIV replication

• Published in: The Journal of clinical investigation 2004-03, Vol.113 (6), p.836-845
• Main Authors: Garber, David A, Silvestri, Guido, Barry, Ashley P, Fedanov, Andrew, Kozyr, Natalia, McClure, Harold, Montefiori, David C, Larsen, Christian P, Altman, John D, Staprans, Silvija I, Feinberg, Mark B
• Format: Article
• Language: English
• Subjects: Animals; CD4-Positive T-Lymphocytes - metabolism; CD8-Positive T-Lymphocytes - metabolism; Enzyme-Linked Immunosorbent Assay; Interferon-gamma - metabolism; Macaca mulatta - virology; Simian Acquired Immunodeficiency Syndrome - metabolism; Simian Immunodeficiency Virus - metabolism; Viral Load; Virus Replication - physiology
• ISSN: 0021-9738
• DOI: 10.1172/JCI200419442

In vivo blockade of CD28 and CD40 T cell costimulation pathways during acute simian immunodeficiency virus (SIV) infection of rhesus macaques was performed to assess the relative contributions of CD4+ T cells, CD8+ T cells, and Ab responses in modulating SIV replication and disease progression. Transient administration of CTLA4-Ig and anti-CD40L mAb to SIV-infected rhesus macaques resulted in dramatic inhibition of the generation of both SIV-specific cellular and humoral immune responses. Acute levels of proliferating CD8+ T cells were associated with early control of SIV viremia but did not predict ensuing set point viremia or survival. The level of in vivo CD4+ T cell proliferation during acute SIV infection correlated with concomitant peak levels of SIV plasma viremia, whereas measures of in vivo CD4+ T cell proliferation that extended into chronic infection correlated with lower SIV viral load and increased survival. These results suggest that proliferating CD4+ T cells function both as sources of virus production and as antiviral effectors and that increased levels of CD4+ T cell proliferation during SIV infections reflect antigen-driven antiviral responses rather than a compensatory homeostatic response. These results highlight the interrelated actions of CD4+ and CD8+ T cell responses in vivo that modulate SIV replication and pathogenesis.